The use of biodegradable or bioerodible polymers to provide sustained or controlled release of drugs or other hormones has been known since the 1960s. (Langer, R. (April 1981) "Controlled Release: A New Approach to Drug Delivery," Technology Review 26-34.) Biodegradable implants for the controlled release of hormones, particularly contraceptive hormones, were developed in the 1970s. (Beck, L. R. and Pope, V. Z. (1984), "Controlled-Release Delivery Systems for Hormones," Drugs 27:528-547.)
A number of biodegradable polymers have been used for controlled release of drugs including polyanhydrides (Mathiowitz, E., et al. (1988), "Polyanhydride Microspheres as Drug Carriers," J. Appl. Polymer Sci. 35:755-774; Lucas, P. A. et al. (1990), "Ectopic induction of cartilage and bone by water-soluble proteins from bovine bone using a polyanhydride delivery vehicle," J. Biomed. Mat. Res. 24:901-911; Masters, D. B., et al. (1993), "Prolonged Regional Nerve Blockade by Controlled Release of Local Anesthetic from a Biodegradable Polymer Matrix," Anesthesiology 79:340-346); and poly(ortho esters) (Heller, J (1990), "Development of poly(ortho esters): a historical overview," Biomaterials 11:659-665).
Aliphatic polyesters comprise another important class of biodegradable polymers. Polymers of polylactic acid (PLA) and polyglycolic acid (PGA) have been used as biodegradable implants for tissue repair for several decades. (See, e.g. Cutright, D. E., et al. (1974), "Degradation rates of polymers and copolymers of polylactic and polyglycolic acids," Oral Surg. 37:142-152; and Gilding, D. K. and Reed, A. M. (1979), "Biodegradable polymers for use in surgery--polyglycolic/polylactic acid homo-and copolymers:1," Polymer 20:1459-1464.)
It has been found that degradation of polyglycolic acid may. take place at essentially the same rate in vivo as in vitro. Schwope, A. D., et al. (1975), "Development of Polylactic/glycolic Acid Delivery Systems for Use in Treatment of Narcotic Addiction," Nat'l Inst. Drug Abuse Res. Monogr. Ser. 4:13-18, appears to disclose that 1/16" diameter beads and rods made from PLA/PGA copolymers to which naltrexone was added by dissolving the polymer and drug in a common solvent and casting, released the drug at the same rate in vivo as in vitro. Drug release in both cases appears to occur by essentially the same mechanism in vivo as in vitro, that is, by hydrolysis in an aqueous environment, and although one report appears to indicate that in the in vivo environment initiation of the degradation process is enhanced (Williams, D. F. (1979), "Some Observations on the Role of Cellular Enzymes in the In-Vivo Degradation of Polymers," in Corrosion and Degradation of Implant Materials, ASTM STP 684, Syrett, B. C. and Acharya, A., eds., American Soc. for Testing and Materials 61-75), later reports appear to indicate that the in vivo degradation rate may be simulated in vitro using phosphate buffer solution. (Gilding, D. K. (1981), "Degradation of Polymers: Mechanisms and Implications for Biomedical Applications," In: Williams, D. F. ed. Fundamental aspects of biocompatibility," CRC Press, 44-65.) Macroscopic devices such as cylinders about 3.times.20 mm of polylactic acid and polyglycolic acid copolymers may degrade at the same rate in vivo as in vitro and cleavage may be due to simple hydrolysis with no enzymatic contributions. (Heller, J. (1984), "Biodegradable Polymers in Controlled Drug Delivery," Critical Reviews in Therapeutic Drug Carrier Systems, 1(1):39-90.)
Aliphatic polyesters such as polymers based on lactic acid, glycolic acid and their copolymers appear to degrade by a bulk erosion process, so that rate of drug release from monolithic devices may not be either linear or predictable. (Heller, J. (1984), "Biodegradable Polymers in Controlled Drug Delivery," Critical Reviews in Therapeutic Drug Carrier Systems, 1(1) :39-90.) These copolymers displaying bulk or homogenous erosion may display significant degradation in the matrix interior, which may result in "dose-dumping" in contrast to surface eroding systems such as those composed of polyanhydrides. (Langer, R. (1990), "New Methods of Drug Delivery," Science 249:1527-1533.)
50:50 glycolic acid:lactic acid copolymers appear to be described as inherently hydrophilic and useful for release of more hydrophobic drugs. (Reed, A. M. and Gilding, D. K. (1981), "Biodegradable polymers for use in surgery--poly(glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro degradation," Polymer 22:494-498.)
A number of controlled release formulations appear to have been made using polylactic/polyglycolic acid copolymers in the form of microparticles or microspheres. U.S. Pat. No. 3,773,919 to Albert, et al. issued Nov. 20, 1973 for "Polylactic-Drug Mixtures" appears to describe various methods for incorporating drugs into the polymer e.g. by coating, mixing the drug with melted polymer, or mixing with a common solvent and drying to form a film or powder. U.S. Pat. No. 4,622,244 to Lapka issued Nov. 11, 1986 for "Process for Preparation of Microcapsules" appears to disclose a process for preparing microspheres comprising active substances coated with polymer useful for injection. U.S. Pat. No. 4,818,542 to DeLuca et al. issued Apr. 4, 1989 "Porous Microspheres for Drug Delivery and Methods for Making Same" appears to disclose polymeric microspheres made with pores in which drugs are incorporated. U.S. Pat. No. 4,897,268 to Tice et al. issued Jan. 30, 1990 for "Drug Delivery System and Method of Making the Same" appears to describe the use of polymers degrading at different rates to form microcapsules for controlled release of active ingredients. U.K. Patent Application 2 234 896 A to Sandoz, Ltd. published Feb. 20, 1991 for "Delayed Release Formulations" appears to describe microparticles formed by a process in which the drug and polymer are dissolved in different phases. Rosilio, V. et al. (1991), "A physiochemical study of the morphology of progesterone-loaded microspheres fabricated from poly(D,L-lactide-co-glycolide), " J. Biomed. Materials Res. 25:667-682 appears to describe progesterone-loaded microspheres of polylactic acid, polyglycolic acid copolymer.
Studies of such microspheres reveal that proteins carried therein may be released before the polymer itself is degraded. (Wang, H. T., et al. (1990), "Degradation of poly(ester) microspheres," Biomaterials 11:679-685.) Nevertheless, microencapsulation with polylactic/polyglycolic copolymer does appear to slow down diffusion of locally administered antibiotics. (Jacob, E., et al. (1991), "Evaluation of Biodegradable Ampicillin Anhydrate Microcapsules for Local Treatment of Experimental Staphylococcal Osteomyelitis," Clin. Orthopaedics and Related Research 267:237-244.) Microspheres made of 75/25 polylactic/polyglycolic acid copolymers and molecular weights of 14 kDa or less appear to have released proteins over a four to six week period. (Cohen, S., et al. (1991), "Controlled Delivery Systems for Proteins Based on Poly(lactic/Glycolic acid) Microspheres," Proceed. Intern. Sympo. Control. Rel. Bioact. Mater. 18:101-102.)
Efforts have been made to improve the predictability of drug release from PGA/PLA microspheres. PCT Publication WO 91/09079 published Jun. 27, 1991 by Farmitalia Carlo Erba S.R.L. for "Use of Supercritical Fluids to Obtain Porous Sponges of Biodegradable Polymers" appears to describe the use of supercritical fluids to manufacture porous microspheres for drug delivery. PCT Publication WO 92/11844 published Jul. 23, 1992 by Enzytech, Inc. for "Stabilization of Proteins by Cationic Biopolymers" appears to describe a method for incorporation of proteins in the form of specific noncovalent complexes with polycationic reagents into sustained release systems which are polymeric microcapsules.
Delivery forms other than microspheres utilizing polylactic acid and polyglycolic acid polymers also appear to have been formulated. U.S. Pat. No. 3,755,558 to Scribner, issued Aug. 28, 1973 for "Polylactide-Drug Mixtures for Topical Application," appears to disclose the preparation of polylactic acid films with active ingredients incorporated therein. A number of methods for incorporation of the active ingredient into the polymer (as described above with respect to U.S. Pat. No. 3,773,919) also appear to have been taught. U.S. Pat. No. 3,887,699 to Yolles issued Jun. 3, 1975 for "Biodegradable Polymeric Article for Dispensing Drugs," appears to disclose the use of shaped polymeric articles such as films, hollow tubing, spheroids useful for injection or oral ingestion, or solid "spaghetti-like" or "fiber-like" configurations for controlled release of drugs wherein the device exudes the drug to the surface of the article. One method of mixing a drug with the polymer is to dissolve both in a suitable solvent, drive off solvent and mold the residue. Large implants and high molecular weight proteins do not appear to be taught as components of the invention described therein. U.S. Pat. No. 3,991,766 to Schmitt et al. issued Nov. 17, 1976 for "Controlled Release of Medicaments using Polymers from Glycolic Acid," appears to disclose filaments comprising PGA and antibiotics. No large proteins appear to be disclosed nor do release kinetics appear to be provided.
U.S. Pat. No. 4,118,470 to Casey et al. issued Oct. 3, 1978 for "Normally-solid, Bioabsorbable, Hydrolyzable, Polymeric Reaction Product," appears to disclose polymeric films for drug delivery. Hollow fibers of polylactic acid polymers also appear to have been described. (Schakenraad, J. M., et al. (1988), "Biodegradable hollow fibres for the controlled release of drugs," Biomaterials 9:116-120.) U.S. Pat. No. 4,801,739 to Franz et al. issued Jan. 31, 1989 for "Oligomeric Hydroxycarboxylic Acid Derivatives, Their Production and Use," appears to disclose polylactic/polyglycolic acid copolymers partially in the form of amides or esters with a sterol as carriers for active ingredients in the form of microparticles, 1 mm rods and films.
U.K. Patent Application No. 2 209 937 A published Jun. 1, 1989 appears to disclose the use of ground polymers as continuous drug release agents. U.S. Pat. No. 4,883,666 to Sabel et al. issued Nov. 28, 1989 for "Controlled Drug Delivery System for Treatment of Neural Disorders," appears to disclose the use of 3 mm diameter discs with pinholes therein for linear release of drugs. U.S. Pat. No. 4,962,091 to Eppstein et al. issued Oct. 9, 1990 for "Controlled Release of Macromolecular Polypeptides" appears to disclose polylactic acid/polyglycolic acid copolymeric films and coated wires which release growth factors including TGF-.beta. over a period of up to 100 days. The polymers appear to comprise a microsuspension of polypeptide and other water-soluble components in which the particles have a diameter of 10 microns or less. EPO Patent Application No. 0 473 268 A2 published Mar. 4, 1992 by Imperial Chemical Industries, PLC appears to disclose the use of 1 mm thick formulations of polypeptide used for continuous release of peptides, including growth hormones, covalently conjugated to the polymer. U.S. Pat. No. 5,134,122 to Orsolini issued Jul. 28, 1992 for "Method for Preparing a Pharmaceutical Composition in the Form of Microparticles," appears to teach a process for preparing a ground polymeric product containing salts of peptides including growth hormones comprising compressing, heating and extruding mixed polymeric powder and salts and grinding the resultant product. A sandwich device for release of insulin appears to be described in Yamakawa, I., et al. (1993), "Controlled Release of Insulin from Plasma-Irradiated Sandwitch Device Using Poly-DL-lactic acid," J. Pharm. Soc. Japan 16:182-187. A very small "implant" injectable through a 16-gauge needle appears to be disclosed in Stoeckemann, K. and Sandow, J. (1993), "Effects of the luteinizing-hormone-releasing hormone (LHRH) antagonist ramorelix (hoe013) and the LHRH agonist buserelin on dimethylbenza!anthracene-induced mammary carcinoma: studies with slow-release formulations," J. Cancer Res. Clin. Oncol. 119:457-462, which appears to have a longer release time and be more clinically effective than microparticles.
Polymeric implants made of polylactic acid and polyglycolic acid polymers and copolymers also appear to have been described. U.S. Pat. No. 4,801,739 to Bays et al. issued Mar. 17, 1987 for "Biodegradable Prosthetic Device," appears to disclose a ventilation tube for the ear in which the degradation rates of various portions of the implant are varied by adjusting the molecular weight of the polymer e.g. with irradiation.
Polymeric implants used for drug release appear to include those formed from polylactic and polyglycolic acid polymers and copolymers. U.S. Pat. No. 3,976,071 to Sadek issued Aug. 24, 1976 for "Methods of Improving Control of Release Rates and Products Useful in Same," appears to describe the effects of active agents dispersed in the polymer versus solid solutions of the active agent in the polymer. U.S. Pat. No. 4,011,312 to Reuter et al. issued Mar. 8, 1977 for "Prolonged Release Drug Form for the Treatment of Bovine Mastitis," appears to disclose a cylindrical bougie for insertion into the teat canal of a polymer and an antimicrobial agent dispersed therein.
U.S. Pat. Nos. 4,048,256, 4,095,600 and 4,122,129 to Casey, et al. issued Sep. 13, 1977, Jun. 20, 1978, and Oct. 24, 1978 respectively, for "Normally-Solid Bioabsorbably Hydrolyzable Polymeric Reaction Product," appear to disclose polymerization methods for producing polymers into which active ingredients may be incorporated. Such devices appear to include sandwich devices, intra-uterine devices, and bandages. U.S. Pat. No. 4,076,798 to Casey et al. issued Feb. 28, 1978 for "High Molecular Weight Polyester Resin, The Method of Making the Same, and the Use Thereof as a Pharmaceutical Composition," appears to be a related patent and also appears to disclose intrauterine devices for releasing drugs.
U.S. Pat. No. 4,293,539 to Ludwig et al. issued Oct. 6, 1981 for "Controlled Release Formulations and Method of Treatment," appears to disclose the incorporation of an active ingredient into a polymer by solubilization of the polymer and active agent in a common solvent and extruding into rods of 2 to 7 mm in diameter and 40 to 80 mm in length, followed by implantation of the rod under the skin of an animal. U.S. Pat. No. 4,832,686 to Anderson issued May 23, 1989 for "Method for Administering Interleukin-2," appears to disclose the use of low molecular weight polylactic acid/polyglycolic acid polymers or copolymers for implants of putty-like consistency for intracranial or other implantation. PCT Patent Publication WO 92/11843 published Jul. 23, 1992 by Alza Corporation for "Bioerodible Devices and Compositions for Diffusional Release of Agents," appears to disclose the preparation of sheets and rods (2 mm diameter.times.1 cm length) with polymers, active ingredients and "required excipients" in which the release rate is not dependent on erosion of the polymer.
Implants of polylactic or polyglycolic acid polymers or copolymers appears to have been used in bone healing applications. Tencer, A. F., et al. (1989), "The effect of local controlled release of sodium fluoride on the stimulation of bone growth," J. Biomed. Materials Res. 23:471-589, appears to disclose dissolution of sodium fluoride and polylactic acid polymer in acetone followed by driving off solvent and rolling into sheets or rods which were inserted into rabbit femurs. The sodium fluoride appears to have been released in a high initial burst followed by a decrease over a period of several days to a steady state. It appears that best healing was shown in rabbits having the sodium fluoride implants after eight weeks.
Biodegradable polymeric scaffold systems seeded with cells appear to be useful for culture of specific types of cells in vitro. U.S. Pat. No. 4,963,489 to Naughton et al. issued Oct. 16, 1990 for "Three-Dimensional Cell and Tissue Culture System," appear to disclose the use of a polymeric matrix which may be made of polyglycolic acid polymers, for culture of cells such as skin, liver, pancreas, bone marrow, osteoblasts and chondrocytes, etc. in vitro. The seeded matrix may be transplanted in vivo. Related U.S. Pat. No. 5,032,508 to Naughton et al. for "Three-Dimensional Cell and Tissue Culture System," contains a similar disclosure. These patents do not appear to disclose incorporation of growth factor into the polymeric matrix. A further related U.S. Pat. No. 5,160,490 to Naughton et al. issued Nov. 3, 1992 for "Three-Dimensional Cell and Tissue Culture Apparatus," appears to disclose that hip prostheses coated with three-dimensional cultures of cartilage may be implanted into patients. This patent also appears to disclose that proteins can be "added to" the matrix or coated on. No methods of "adding" such proteins or release kinetics appear to be described.
Polymeric scaffolds seeded with cells for cellular growth and implantation for cartilage regeneration made from polyglycolic acid/polylactic acid copolymers appear to be disclosed in U.S. Pat. No. 5,041,138 to Vacanti, et al. issued Aug. 20, 1991 for "Neomorphogenesis of Cartilage in Vivo from Cell Culture." This patent appears to teach that growth factors may be incorporated into the polymers but does not appear to provide any methods for doing so. The patent also appears to teach that implantation of the polymeric scaffolding alone without chondrocytes does not result in cartilage formation. Freed, L. E., et al. (1993), "Neocartilage formation in vitro and in vivo using cells cultured on synthetic biodegradable polymers" J. Biomed. Materials Res. 27:11-23, appears to disclose the use of cell-seeded porous polylactic acid and fibrous polyglycolic acid polymers to prepare cartilaginous implants for use in reconstructive or orthopaedic surgery. Apparently no growth factors were added to the polymers. Vacanti, C. A., et al. (1993), "Tissue Engineered Growth of Bone and Cartilage," Transplantation Proc. 25:1019-1021, appears to disclose the use of cell-seeded polyglycolic acid polymeric mesh for implantation on the backs of nude mice to grow bone and cartilage. The use of growth factors in the polymer does not appear to be described. In a review article by Langer, R. and Vacanti, J. P. (1993), "Tissue Engineering," Science 260:921-926, cell seeded scaffolds for in vitro growth of cartilage and bone appear to be described and it is stated that TGF-.beta. is important in bone repair and that effective delivery systems for this agent will be important.
A number of growth factors appear to have been found to be important in the healing of bone and cartilage, including bone morphogenic protein (BMP) platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-.beta. (TGF-.beta.) (Hollinger, J. and Chaudhari, A (1992), "Bone Regeneration Materials for the Mandibular and Craniofacial Complex," Cells and Materials 2:143-151). As reported in Edelman, E. R. and Nugent, M. A. (1991), "Controlled Release of Basic Fibroblast Growth Factor," Drug News & Perspectives 4:352-357, basic fibroblast growth factor (bFGF) appears to be a mitogen for many different cells. However, this growth factor appears to lose most of its activity when subjected to organic solvents and heat in making controlled release implants. Edelman, E. R., et al. (1991), "Controlled and modulated release of basic fibroblast growth factor," Biomaterials 12:619-626, appears to state that polypeptide growth factors have in vivo half lives on the order of seconds to minutes, and that bFGF, a mitogen for fibroblasts and a potent angiogenesis factor useful in tissue repair, is best released by binding to heparin-Sepharose beads. U.S. Pat. No. 5,100,668 to Edelman et al. issued Mar. 31, 1992 appears to discuss systems for controlled release of bFGF, and apparently reveals a high initial release.
Hollinger, J. O., et al. (1990), "Osseous wound healing with xenogeneic bone implants with a biodegradable carrier," Surgery 107:50-54, appears to discuss experiments using implants comprising 50:50 polylactic/polyglycolic acid copolymer made by adding bone morphogenic protein (BMP) to polymer solution in acetone followed by vacuum curing for craniotomy repair. The article appears to report that contrary to earlier reports of successful bone regeneration using BMP, the study could not support such data. Bone morphogenetic protein-2 appears to have been found to improve bone healing in implants having a demineralized dog bone powder matrix (Toriumi, D. M. (1991), "Mandibular Reconstruction with a Recombinant Bone-Inducing Factor," Arch. Otolaryngol. Head Neck Surg. 117:1101-1112.) Heckman, J. D., et al. (1991), "The Use of Bone Morphogenetic Protein in the Treatment of Non-Union in a Canine Model," J. Bone and Joint Surg. 73-A:750-764, appears to describe implants mimicking the size and shape of bone defects made of bone morphogenetic protein copolymerized with polylactic acid as useful in bone healing. Alper, J. (1993), "Will bone morphogenic proteins pay off?" Bio/Technology 11:649-651, appears to disclose that BMP in a bone powder matrix is used for fracture healing and causes cell differentiation. Marden, L. J. et al (1993), "rhBMP-2/ICBM is superior to DBM in repair of rat craniotomies," J. Dent. Res. Abstracts No. 130, appears to disclose that recombinant BMP in an insoluble collagenous bone matrix provides superior bone healing. Kleinschmidt, J. C. et al. (1993), "A Multiphase System Bone Implant for Regenerating the Calvaria," appears to disclose the use of two biodegradable polymeric disks with bone morphogenetic protein between them placed in craniotomy sites of rabbits to aid in healing and prevent prolapse of soft tissue in the defect.
Thyroid-derived chondrocyte stimulating factor (TDCSF) appears to be described in PCT Publication WO 92/14749 by The Board of Trustees of the Leland Stanford Junior University Sep. 3, 1992, as useful for the culture of chondrocytes in vivo and for developing cartilage implants in vitro and for in vivo use in cartilage and bone defect repair. It does not appear that any methods for making implants or release kinetics are taught. PCT Publication WO 93/15767 by Merck & Co, Inc. Aug. 19, 1993 appears to disclose implants made of bioerodible polymers selected from poly(orthoester) or polyacetal and a prostaglandin or .beta.-estradiol implanted at the site of desired bone growth as useful in bone healing.
Transforming Growth Factor .beta. (TGF-.beta.) has been studied for its effects on cell growth. Silberstein, G. B. and Daniel, C. W. (1987), "Reversible Inhibition of Mammary Gland Growth by Transforming Growth Factor--.beta.," Science 237:291-293 appears to report that slow-release polymeric pellets (made of ethylene vinyl acetate copolymer) inhibited mouse mammary growth. U.S. Pat. No. 5,053,050 to Itay issued Oct. 1, 1991 for "Compositions for Repair of Cartilage and Bone," appears to disclose a biodegradable viscoelastic matrix dipped in a solution comprising chondrocytes or osteoblasts which have been cultured in a medium containing TGF-.beta. used for bone and cartilage repair. The growth factor does not appear to be incorporated into the polymer.
Hollinger, J. and Chaudhari, A (1992), "Bone Regeneration Materials for the Mandibular and Craniofacial Complex," Cells and Materials 2:143-151 appears to disclose that TGF-.beta. is released in a latent form at a fracture site, and activated by proteolytic enzymes. In its activated form, TGF-.beta. may be involved in bone remodeling, promote conversion of mesenchymal cells into cartilage cells and enhance production of collagen, fibronectin and plasminogen activating factor in osteoblasts. TGF-.beta. belongs to a family of factors, including two cartilage induction factors previously known as CIF-A and CIF-B, now known as TGF-.beta..sub.1 and TGF-.beta..sub.2, inhibin, and the BMP's. TGF-.beta. is known for its antiproliferative effects on cells, particularly epithelial cells, but inhibition is also common for mesenchymal cells such as fibroblasts and endothelial cells. In some cases such effects correlate with augmented cellular differentiation. TGF-.beta. has been shown to have both stimulatory and inhibitory effects on proliferation of cultured osteoblasts in different studies. It has been shown to be crucial for wound healing, and is transformed to its active form under acidic conditions such as those produced by bone resorption or macrophages.
Drug release kinetics from a polylactic acid/polyglycolic acid copolymer related to Nafarelin, a peptide hormone, have been reported in Sanders, L. M., et al. (1986), "Prolonged Controlled-Release of Nafarelin, a Luteinizing Hormone-Releasing Hormone Analogue, From Biodegradable Polymeric Implants: Influence of Composition and Molecular Weight of Polymer" J. Pharm. Sciences 75:356-360. The implant appears to have been prepared by melt extrusion of a blend of the compound with the polymer and release has a triphasic profile characterized by a secondary phase of lower release preceded and followed by phases of higher release.
Lewis, D. H. (1990), "Controlled Release of Bioactive Agents from Lactide/Glycolide Polymers," in Biodegradable Polymers as Drug Delivery Systems, Chasin, M. and Langer, R., eds, New York, 1-41, appears to disclose a number of factors affecting drug release kinetics. This reference also appears to report that growth hormones in these systems have at best been able to provide only about two week's duration of biological activity.
U.S. Pat. No. 5,004,602 to Hutchinson issued Apr. 2, 1991 for "Continuous Release Pharmaceutical Compositions Formed by Freeze Drying Acetic Acid Solutions of Polylactide" and related U.S. Pat. No. 4,767,628 to Hutchinson issued Aug. 30, 1988 for "Continuous Release Pharmaceutical Compositions," appear to disclose the use of low molecular weight polymers to cause the two phases of release caused by matrix diffusion and degradation of polymer to overlap.
Hollinger, J. (1993), "Factors for Osseous Repair and Delivery: Part II," reviews factors important in bone healing such as porosity of implants, and states that information relative to optimal pore sizes for osteoconduction is lacking. The article further appears to disclose that by manipulating the biodegradation of the delivery system, the release kinetics of regenerative factors can be tailored for the wound healing chronobiological continuum, and states that chondroosteogenic factor is not needed after the fifth day. Microencapsulating cytokines (bone growth and inductive factors) for pulsed release two to five days after implantation is apparently recommended.
K. Athanasiou et al. (1993), "Use of Biodegradable Implants for Repairing Large Articular Cartilage Defects in the Rabbit," Proc. 38th Ann. Mtg. Orthopaedic Research Soc. Feb. 18, 1992, discloses that 50:50 poly lactide-co-glycolide polymeric implants having an average molecular weight of 12-15 kD and containing demineralized bone powder used to fill osteochondral cylindrical defects of 4.0 mm diameter and 6 mm depth degraded over a period of 8 weeks under conditions of functional joint loading. Successful bone and cartilage repair were observed. Residual polymer was observed to be present at 8 weeks.
U.S. patent application 07/914,992 filed Jul. 16, 1992 discloses a resorbable implant based on independently gelling polymers of a single enantiomeric lactide. Said implant is capable of carrying a bioactive compound; however, said bioactive material is not released in a continuous manner over a period as long as eight weeks.